US7253163B2 - Benzothiazine and benzothiadiazine compounds - Google Patents

Benzothiazine and benzothiadiazine compounds Download PDF

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US7253163B2
US7253163B2 US10/865,185 US86518504A US7253163B2 US 7253163 B2 US7253163 B2 US 7253163B2 US 86518504 A US86518504 A US 86518504A US 7253163 B2 US7253163 B2 US 7253163B2
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pyrrolo
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phenoxy
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Patrice Desos
Alex Cordi
Pierre Lestagé
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to new benzothiazine and benzothiadiazine compounds, to a process for their preparation and to pharmaceutical compositions containing them.
  • the compounds of the present invention are new and have very valuable pharmacological properties in respect of AMPA receptors.
  • the AMPA ( ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor appears to be involved to the greatest extent in the phenomena of physiological neuronal excitability and, especially, in those phenomena involved in memorisation processes. For example, it has been shown that learning is associated with an increase in the binding of AMPA to its receptor in the hippocampus, one of the areas of the brain essential to processes of memory and cognition. Likewise, nootropic agents such as aniracetam have very recently been described as modulating the AMPA receptors of neuronal cells in a positive manner (Journal of Neurochemistry, 1992, 58, 1199-1204).
  • patent specification EP 692 484 describes a benzothiadiazine compound having a facilitating action on the AMPA current
  • patent application WO 99/42456 describes inter alia particular benzothiadiazine compounds as modulators of AMPA receptors.
  • the benzothiazine and benzothiadiazine compounds to which the present invention relates besides being new, surprisingly exhibit pharmacological activity on the AMPA current that is markedly superior to the activity of the compounds having similar structures described in the prior art. They are useful as AMPA modulators for the treatment or prevention of disorders of memory and cognition that are associated with age, with syndromes of anxiety or depression, with progressive neurodegenerative diseases, with Alzheimer's disease, with Pick's disease, with Huntington's chorea, with schizophrenia, with the sequelae of acute neurodegenerative diseases, with the sequelae of ischaemia and with the sequelae of epilepsy.
  • n 1, 2 or 3
  • R 1 preferably represents a monocyclic heterocyclic group.
  • R 1 representing an aromatic monocyclic heterocyclic group containing from 1 to 4 hetero atoms selected from nitrogen, sulphur and oxygen, more especially nitrogen and oxygen, such as, for example, the tetrazolyl, triazolyl, imidazolyl, pyrazolyl, pyrrolyl, pyridyl, furyl, oxazolyl and oxadiazolyl groups.
  • R 1 represents a monocyclic heterocyclic group containing from 1 to 4 hetero atoms selected from oxygen, sulphur and nitrogen, more especially the oxathiadiazolyl, dihydrooxadiazolyl and morpholinyl groups.
  • the group R 1 is unsubstituted or substituted by a linear or branched (C 1 -C 6 )alkyl group such as, for example, the methyl group, or by an oxo or thioxo group.
  • the R 1 group is preferably in the meta- or para-position of the phenoxy ring structure carrying it.
  • R 2 group being a hydrogen atom.
  • Preferred compounds of the invention are compounds wherein A represents a nitrogen atom and, together with the adjacent —CHR 3 — group, forms the ring
  • m represents 1, 2 or 3, preferably 1.
  • Preferred compounds of the invention are 7-[3-(1H-tetrazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide, 7-[3-(3-furyl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide and 7-[3-(1,3-oxazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine.
  • the invention relates also to the processes for the preparation of compounds of formula (I).
  • R′ 1 , R′ 2 and R 3 are as defined hereinbefore, which is:
  • R′ 1 , R′ 2 and R 3 are as defined hereinbefore,
  • R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore,
  • R 3 is as defined for formula (I),
  • R 1 , R 2 , R 3 and R 4 are as defined for formula (I),
  • R′ 1 and R′ 2 are as defined hereinbefore,
  • R′ 1 , and R′ 2 are as defined hereinbefore,
  • R′ 1 , and R′ 2 are as defined hereinbefore,
  • R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore,
  • R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore and R′ 5 represents a halogen atom
  • R 2 , R 3 , R 4 and R 5 are as defined for formula (I),
  • R′′ 1 represents a cyano group or a heterocycle
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined for formula (I),
  • the invention relates also to pharmaceutical compositions comprising, as active ingredient,
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragèes, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
  • the useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient and ranges from 1 to 500 mg per day in one or more administrations.
  • the starting materials used are products that are known or that are prepared according to known operating procedures.
  • Step A 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenol
  • a solution of 68.75 mmol of BBr 3 in 25 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 27.50 mmol of 7-methoxy-2,3-dihydro-1H-pyrrolo-[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide in 350 ml of methylene chloride.
  • Stirring is carried out at ambient temperature for 24 hours.
  • the reaction mixture is poured into a mixture of ice and water, and the suspension is stirred for 30 minutes.
  • the precipitate is filtered off, rinsed several times with water, filtered under suction and dried in vacuo to yield the expected product.
  • Step B 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzonitrile
  • a suspension containing 7.06 mmol of the product described in the Step above, 11.02 mmol of 3-cyanophenylboronic acid, 11.02 mmol of copper(II) acetate, 22 mmol of pyridine and about 500 mg of 4 ⁇ molecular sieve in 200 ml of methylene chloride is stirred for 24 hours.
  • the reaction mixture is diluted by adding a further 100 ml of methylene chloride and the suspension is filtered.
  • the filtrate is concentrated and then directly placed on a silica column which is eluted with a methylene chloride/methanol 95/5 system.
  • the fractions containing the expected product are combined and evaporated, and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the expected product is recovered in the form of a white powder.
  • Step C 7-[3-(1H-Tetrazol-5-yl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine 5,5-dioxide
  • Step D 7-[3-(1H-Tetrazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step A 7-[3-(1-Methyl-2H-tetrazol-5-yl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step B 7-[3-(1-Methyl-2H-tetrazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step A 7-[3-(2-Methyl-2H-tetrazol-5-yl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazine 5,5-dioxide
  • Step B 7-[3-(2-Methyl-2H-tetrazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Examples 4 to 12 which follow were prepared according to the procedure described in Example 1, using the appropriate boronic acid in Step B and converting the functional group into the heteroaryl desired.
  • Step A 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]-N′-hydroxybenzenecarboximidamide
  • Step B 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]-N′-[(ethoxycarbonyl)oxy]benzenecarboximidamide
  • Step C 3- ⁇ 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl ⁇ -1,2,4-oxadiazol-5(4H)-one
  • Step D 3- ⁇ 3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl ⁇ -1,2,4-oxadiazol-5(4H)-one
  • Step A 3- ⁇ 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl ⁇ -1,2,4-oxadiazole-5(4H)-thione
  • Step B 3- ⁇ 3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl ⁇ -1,2,4-oxadiazole-5(4H)-thione
  • Step A 7-[3-(2-Oxido-3H-1,2,3,5-oxathiadiazol-4-yl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step B 7-[3-(2-Oxido-3H-1,2,3,5-oxathiadiazol-4-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step A 7-(3-Bromophenoxy)-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step B 7-[3-(2-Furyl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step C 7-[3-(2-Furyl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step A 7-[3-(3-Furyl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step B 7-[3-(3-Furyl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step A 7-(3-Pyridin-2-ylphenoxy)-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step B 7-(3-Pyridin-2-ylphenoxy)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine 5,5-dioxide
  • Step A 4-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)-oxy]benzonitrile
  • Step B 7-[4-(1H-Tetrazol-5-yl)phenoxy]-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazine 5,5-dioxide
  • Step C 7-[4-(1H-Tetrazol-5-yl)phenoxy]-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine 5,5-dioxide
  • Step A Methyl 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzoate
  • Step B 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzohydrazide
  • Step C 5- ⁇ 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl ⁇ -1,3,4-oxadiazol-2(3H)-one
  • Step D 5- ⁇ 3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl ⁇ -1,3,4-oxadiazol-2(3H)-one
  • mRNA's are prepared from cerebral cortex of male Wistar rats by the guanidinium thiocyanate/phenol/chloroform method.
  • the poly (A + ) mRNA's are isolated by chromatography on oligo-dT cellulose and injected at a level of 50 ng per oocyte.
  • the oocytes are incubated for 2 to 3 days at 18° C. to permit expression of the receptors and are then stored at 8-10° C.
  • Electrophysiological recording is carried out in a Plexiglass® chamber at 20-24° C. in OR2 medium (J. Exp. Zool., 1973, 184, 321-334) by the “voltage-clamp” method using two electrodes, with a third electrode placed in the bath serving as reference.
  • AMPA is used in a concentration of 10 ⁇ M.
  • concentration that doubles (EC2X) or quintuples (EC5X) the intensity of the current induced by AMPA alone (5 to 50 nA) is determined.
  • the compounds of the invention potentiate the excitatory effects of AMPA to a very considerable degree and their activity is very clearly superior to that of compounds of reference.
  • the compound of Example 1 especially has an EC2X of 0.2 ⁇ M and an EC5X of 0.8 ⁇ M, the compound of Example 17 an EC2X of 4.5 ⁇ M and an EC5X of 11.5 ⁇ M, the compound of Example 18 an EC2X of 0.66 ⁇ M and an EC5X of 4 ⁇ M.

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US9493484B2 (en) 2012-02-08 2016-11-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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SG139548A1 (en) 2008-02-29
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AU2004202585A1 (en) 2005-01-06
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